Novel testosterone ester formulation for human use

ABSTRACT

Disclosed is a formulation of testosterone decanoate for use in the treatment of humans. In contrast with known formulations comprising testosterone decanoate, it was found that any other esters of testosterone normally present together with testosterone decanoate, can be omitted and the formulation thus comprises testosterone decanoate as the sole ester of testosterone.

FIELD OF THE INVENTION

The invention is in the field of the treatment of androgen-insufficiencyrelated disorders, by the inducement into a human being of an adequatelevel of testosterone. The invention particularly pertains to a methodof treatment in which a desired level of testosterone is induced by theadministration of a medicament or, otherwise, to the manufacture of amedicament in such a treatment, wherein the medicament is apharmaceutical formulation in the form of an oily solution for injectioncomprising testosterone decanoate dissolved in a pharmaceuticallyacceptable oily medium.

BACKGROUND ART

Testosterone decanoate has been known as a potential therapeuticcompound administered in animal trials since the thirties of the 20^(th)century. Thus, in GB 465,331 (published 1937), testosterone capric acid(decanoic acid) ester is disclosed among several other testosteroneesters. Other publications related to animal testing involvingtestosterone decanoate are Verheul et al. (1986) and Ågmo et al. (1996).

Verheul, H. A. M. et al., Effects of sex, gonadectomy and severalsteroids on the development of insulin-dependent diabetes mellitus inthe BB rat, Clin. Exp. Immunol (1986) 63, 656-662 describes aninvestigation into the question of whether several sex and steroidrelated factors, such as treatment with several steroids, includingtestosterone decanoate, affect the development of diabetes mellitus inBB rats, quod non. Ågmo, A. et al., Dopamine and sexual behavior in themale rabbit in Pharmacology Biochemistry & Behavior, Vol. 55, No.2, pp.289-295 (1996) describes the administration of testosterone decanoate asone of several different methods of preparing certain rabbits so as tohave suitable test animals for investigating the influence of dopamineon sexual behavior. Particularly, the testosterone decanoate treatmentserves to provide test animals maintaining a low but stable level ofsexual behaviour.

Despite this long-standing use in science, the compound per se has neverreached a stage of use in human therapy in practice. Also a recent paperby Kamischke et al., in summarizing the state of the art with regard toesters of testosterone, mentions testosterone undecanoate andtestosterone buciclate as being suitable in practice for use in malecontraception, and is silent on testosterone decanoate (Axel Kamischkeet al., Clinical Endocrinology (2000), 53, 43-52, see page 43). Otherbackground publications on male contraception include papers by M.Cristina Meriggiola et al. (Fertility and Sterility Vol. 68, No. 5(1997), pp 844-850 and Human Reproduction vol. 13 no. 5, pp. 1225-1229,1998) which relate to male contraception by treatment with theanti-androgenic progestagen cyproterone acetate and either testosteroneundecanoate or testosterone enanthate. Testosterone enanthate is alsoknown as the androgen component in studies involving the progestagendesogestrel (inter alia in Frederick C. W. Wu et al., Journal ofClinical Endocrinology and Metabolism 84 (1), pp 112-122). None of thesepapers relate to using testosterone decanoate. One recent reference totestosterone decanoate is WO 97/41865, in which the compound isgenerally included in a broad range of summed-up esters of testosterone.In some patent documents originating from the seventies (BE 855163, U.S.Pat. No. 4,220,599 (DE 2508615), U.S. Pat. No. 4,071,623) testosteroneesters of a chain length typically including decanoate are disclosed fororal administration. No teaching is provided on parenteraladministration. From these disclosures at any rate the undecanoate wouldbe considered as better suitable for oral administration. Indeed,testosterone undecanoate rather than the decanoate has become availableas a preparation for oral use (marketed inter alia under the tradenameAndriol® in several countries).

Still, the compound testosterone decanoate is not entirely devoid ofpractical utility, as a formulation of the above-identified type, i.e.one in the form of an oily solution for injection comprisingtestosterone decanoate dissolved in a pharmaceutically acceptable oilymedium, is known, and is available on the market in a great number ofcountries worldwide, in many cases under the name of Sustanon®250.Sustanon®250 is an oily solution comprising four esters of testosterone,viz. testosterone propionate, testosterone phenylpropionate,testosterone isocaproate and testosterone decanoate. Each of the estershaving a different pharmacokinetic profile, all of them have beenconsidered essential for obtaining both a rapid onset (the smalleresters) and a long duration of action (the decanoate).

As background art, besides Sustanon®250, it can be mentioned that H. M.M. Behre and E. Nieschlag have published a chapter on comparativepharmacokinetics of testosterone esters in Testosterone, Chapter 11,pages 329-348 (1998). Even in this standard text on testosterone estersno information on the independent use of testosterone decanoate isgiven.

SUMMARY OF THE INVENTION

It has now been found, and surprisingly so, that—contrary to thepractice of including testosterone decanoate only in a judicious mixtureof esters—testosterone decanoate alone provides an onset of action and aduration of action at least comparable to that of the mixture. This hasled to the present invention, which resides in omitting three of thefour esters as compared to the known mixture and thus provides aformulation of the above-indicated type, characterized in thattestosterone decanoate is the sole ester of testosterone present in theoily medium.

DETAILED DESCRIPTION OF THE INVENTION

Testosterone decanoate being a compound which in effect serves toadminister the male hormone testosterone, the formulation of theinvention can be used in the treatment of androgen-insufficiency relateddisorders. In the context of the invention, the term “androgeninsufficiency” is to be understood to pertain to all kinds of diseases,disorders, and symptoms in which a male or a female suffers from too lowa testosterone level, such as in hypogonadal men. In particular, theandrogen insufficiency to be treated by the formulation of the inventionis the reduction of the testosterone level which a human male incurs asa result of age (the formulation of the invention is then used for malehormone replacement therapy), or when he is subject to malecontraception. In the context of male contraception, the formulation ofthe invention especially serves to neutralize the effect of regimens ofmale hormone contraception in which a sterilitant such as a progestagenor LHRH (luteinizing hormone releasing hormone) is administeredregularly, e.g. daily, or it is used as the sole male contraceptivesubstance.

The formulation of the invention can be prepared by dissolvingtestosterone in a suitable amount of an oily medium, such as arachisoil, oleic acid, castor oil, and the like, including mixtures of oils.The amount of testosterone that can be dissolved differs per chosenmedium, but will generally be within the range of from 100-400 mg/ml.The preferred oil is castor oil. Not only does this lead to a favorableoverall stability (no or little crystallization and no re-esterificationof testosterone), it particularly has an unexpectedly good releaseprofile, with burst staying within the therapeutic window. Moreover itdisplays a good solubility of testosterone decanoate, the concentrationthereof preferably being up to 200 mg/ml.

Additives common to injection fluids can be added to the solution ifdesired. Suitable additives are known to the person skilled in the art.Possible additives include liquids that serve to lower the viscosity ofthe fomulation, e.g. benzyl alcohol, benzyl benzoate, or benzylpropionate. Because of the way of administration, through injection, itis preferred to have as few additives in the solution as possible. Thisis customary in the art of making injection fluids, and does not requireelucidation here.

The invention also pertains to the use of testosterone decanoate for themanufacture of a medicine in the treatment of androgen-insufficiencydisorders wherein testosterone decanoate is the sole androgen.Particularly, it has been found that testosterone decanoate, as the soleandrogen, can be used advantageously in male contraception. This isnotably so in a contraceptive regimen wherein the progestagenetonogestrel is employed to provide azoospermia, and testosteronedecanoate is used to provide the required androgen supplementation. Thiscombination of progestagen and androgen provides a relatively rapidonset of azoospermic effect, and provides a steady level oftestosterone. In the context of the invention, azoospermia is consideredto be found if 90% or more of the men receiving treatment exhibitazoospermia.

After intramuscular administration, testosterone levels will increaserapidly to high normal levels, with a peak (ca. 20-30 nmol/L) during thefirst few days. This comes as a surprise in view of what is known fromSustanon®250, namely that testosterone decanoate serves to attainprolonger duration of action, while the three shorter-chained estersserve to shift the onset of action to an earlier point in time. In theproduct of the invention, after the first few days, the testosteronelevels will gradually decline to low physiological levels (ca. 12nmol/L) after four or eight weeks, depending on the dose.

The invention further pertains to a method of treatment ofandrogen-insufficiency disorders, comprising administering to a human,notably a human male, in need thereof an effective amount of anandrogen, wherein the sole androgen administered is testosteronedecanoate. As above, the method is particularly well-suited to treatandrogen-insufficiency which occurs as a result of deliberateprogestagen-induced azoospermia (male contraception), notably when theprogestagen is etonogestrel.

A preferred male contraceptive regimen is provided for by a kit (a drugdelivery system) comprising a formulation of testosterone decanoate asdescribed above, and etonogestrel in the form of oral daily tabletshaving a strength of 150-600 μg etonogestrel, preferably 150-300 μg.Alternatively, the etonogestrel is administered by means of one or moresubcutaneous implants to release 40 to 200 μg etonogestrel per day,preferably 120 to 180 μg. Comparable implants are known from femalecontraception, e.g., under the name of Implanon®. For the manufacture ofsuch implants, reference is made to EP 303 306. For a preferredcontraceptive regimen, in the case of oral administration ofetonogestrel, the dose in men will be approximately four and two timesas high as that for desogestrel in the female OCs Cerazette® (75 μgdesogestrel) and Marvelon® (150 μg desogestrel) respectively. When itcomes to etonogestrel implants, preferably three times the release ofprogestagen is used as compared to the amounts administered to women,viz. three Implanon® 4 cm implants. More preferably two implants areused, each having 1.5 times the length of Implanon, or one singleimplant of more restricted length (e.g. 4-5 cm) providing a higherrelease. The implants are intended to be applied and removed yearly,although a longer action is not excluded. The androgenic component ofthe regimen according to the invention is preferably an injection of 300mg to 700 mg, and preferably 400 to 600 mg testosterone decanoate givenonce per four weeks to eight weeks, and preferably once per six weeks.It is most preferred to give 600 mg once per six weeks, or 400 mg perfour weeks. If desired, formulations can be provided which containadditives so as to provide a reduced and more prolonged level oftestosterone (e.g. 800 to 1000 mg per 12 weeks using, e.g. a substantialamount of additive, such as 50% by weight of benzyl benzoate). This isformulation practice well-known to the skilled person. The drug deliverysystem according to the invention will preferably contain appropriateinstructions as to the regimen of administration to be used in theprovided method of treatment.

An unexpected advantage of this testosterone treatment is the relativelyrapid onset of action, as displayed by the short time to reach atherapeutic level, much faster than could be expected on the basis ofthe common general knowledge of Sustanon®250.

In the contraceptive regimens based on etonogestrel combined with TD,azoospermia can be achieved well within 24 weeks, or even in a durationcomparable to that in the case of vasectomy, which generally is 12-16weeks. The invention will be further illustrated with reference to theExamples which follow.

EXAMPLE 1 Preparation of Solution

Solutions of 200 mg/ml testosterone decanoate in castor oil are preparedby dissolving 1000 g of testosterone decanoate in about 3.5 L of thesolvent at 50° C. Thereafter, solvent is added up to 5 L. A clearsolution is obtained, without visible particles of undissolved matter.After filtration the solution is ready for use.

EXAMPLE 2 Test in Hypogonadal Men

To eight hypogonadal men an intramuscular injection of 500 mgtestosterone decanoate in 2 ml arachis oil is given. Testosterone levelsare measured at regular intervals for a period of 50 days. The resultsshow a rapid onset of action in that an average therapeutic level oftestosterone of 25 nmol/l is reached within 1.5 day (mean value), peaklevel is reached within 5 days, and a therapeutic level of more than 10nmol/l is seen up to 30 days.

EXAMPLE 3 Test in Hypogonadal Men

To eight hypogonadal men an intramuscular injection of 400 mgtestosterone decanoate in 2 ml castor oil is given. Testosterone levelsare measured at regular intervals for a period of 50 days. The resultsshow a rapid onset of action in that an average therapeutic level oftestosterone of 25 nmol/l is reached within 2 days peak level is reachedwithin 8 days, and a therapeutic level of more than 10 nmol/l is seen upto 42 days (all mean values).

In FIG. 1, the results of Examples 2 and 3 are presented in a graph. Onthe x-axis the number of days after administration is indicated, on they-axis the determined blood levels of testosterone.

Comparison

The results attained in the foregoing Examples are compared with theresults of (A) Sustanon®250, 250 mg in 1 ml of arachis oil (J. A.Cantrill et al., Clin. Endocrinol. 1984;21;97-107, p 102), and withtestosterone undecanoate, 1000 mg in (B) 4 ml of castor oil and (C) twotimes 4 ml of tea seed oil (H. M. M. Behre et al., European Journal ofEndocrinology (1999) 140 414-419. The results are depicted in the tablebelow. The formulations of the invention unexpectedly provide an onsetof action comparable to that of Sustanon®250 and more rapid thantestosterone undecanoate. TABLE Onset of action Duration of actionPreparation (25 nmol/l level) (>10 nmol/l) Example 2 1.5 days 30 daysExample 3   2 days 42 days (A) 1.5 days 21 days (B)   7 days 42 days (C)  6 days 50 days

1. A pharmaceutical formulation, comprising: an oily solution forinjection, comprising testosterone decanoate dissolved in an acceptableoily medium, wherein testosterone decanoate is the sole ester oftestosterone present in the oily medium.
 2. The pharmaceuticalformulation according to claim 1, wherein the testosterone decanoateconcentration is 100-400 mg/ml.
 3. The pharmaceutical formulationaccording to claim 2, wherein the oily medium is castor oil. 4-6.(canceled)
 7. A method of treatment of androgen-insufficiency disorders,comprising: administering to a patient in need thereof an effectiveamount of an androgen, wherein the sole androgen administered istestosterone decanoate.
 8. A drug delivery system for malecontraception, comprising: a vehicle for administering a progestagen anda vehicle for administering an androgen, wherein the progestagen isetonogestrel and the androgen is testosterone decanoate.
 9. The drugdelivery system according to claim 8, wherein the vehicle foradministering etonogestrel is a subcutaneous implant, and the vehiclefor administering the androgen is a subcutaneous injection fluid. 10.The drug delivery system according to claim 9, wherein the implant isreleasing 40 to 200 μg etonogestrel a day.
 11. The drug delivery systemaccording to claim 9, wherein the injection fluid is a pharmaceuticalformulation, comprising: an oily solution for injection, comprisingtestosterone decanoate dissolved in an acceptable oily medium, whereintestosterone decanoate is the sole ester of testosterone present in theoily medium.
 12. The drug delivery system according to claim 8,providing instructions for administering testosterone decanoate in aregimen of 300 to 700 mg once every four to eight weeks.
 13. The drugdelivery system according to claim 10, wherein the implant is releasing120 to 180 μg a day.
 14. The drug delivery system according to claim 12,wherein the regimen is 400 mg once per four weeks.